tbuckley/cabot-search huggingface dataset:
Abstract 3653: The moderating role of dietary patterns on physical health and risk of cancer mortality in the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort
Authors: Akwasi O. Aduboffour, Stephen J. Carter, George Howard, Saira Khan, Marquita Lewis-Thames, Justin Xavier Moore, MPH X. Moore
Journal: Cancer Research (2022)

Abstract Diet and physical activity share an association with cancer mortality. We investigated whether empirically-defined dietary patterns modified the association between a composite of physical health and cancer mortality. METHODS: We performed analysis among participants from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. Physical health (PH) composite was assessed by the product of baseline heart rate and systolic blood pressure, a reliable measurement of myocardial oxygen demand, and self-reported physical activity. Participant adherence was assessed with empirically-defined dietary patterns including: Convenience (including Chinese and Mexican foods, pasta, pizza), Plant-based (including fruits, vegetables), Southern (including added fats, fried foods, sugar-sweetened beverages), Sweets/Fats (including sugary foods) and Alcohol/Salads (including alcohol, green-leafy vegetables, salad dressing) was examined as an effect modifier. We performed comparisons across PH composite risk groups (i.e., severe, high, moderate, and low risk). We estimated hazard ratios (HRs) and associated 95% confidence intervals (CIs) by PH composite groups, stratified by dietary patterns. RESULTS: Among 20,857 participants, 18% were defined as severe-risk PH, 30% were high-risk, 15% were moderate-risk PH, and 38% were low-risk PH. The most common dietary pattern adhered to by severe-risk PH participants was the southern based diet (30% adhering, p value &amp;lt;0.01). Severe-risk PH participants generally had higher risks for cancer mortality, corresponding to a 2.4-fold increased risk of cancer mortality (adjusted HR: 2.42; 95% CI: 1.52 - 3.85) even with limited southern diet consumption (1st quartile). CONCLUSIONS: Dietary patterns influence cancer mortality risk; however cardiovascular health is independently associated with greater long-term risk of cancer death. Citation Format: Akwasi O. Aduboffour, Stephen J. Carter, George Howard, Saira Khan, Marquita Lewis-Thames, Justin Xavier Moore, PhD, MPH X. Moore. The moderating role of dietary patterns on physical health and risk of cancer mortality in the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3653.
Abstract 2365: Mechanisms of mutant p53 targeting to the genome
Authors: Stephanie Metcalf, Stevie Morris, Peter Hollenhorst
Journal: Cancer Research (2022)

Abstract Mutations in genes often result in tumor formation, especially when these mutations occur in tumor suppressors. TP53 is a tumor suppressor that is frequently mutated in cancer, with mutations in this gene occurring in nearly 50% of all cancer cases. Once mutated, p53 loses its tumor suppressive function while simultaneously gaining oncogenic function. One of the functions that mutant p53 loses is the ability to directly bind to chromatin, however, it has been reported that mutant p53 can still affect the transcriptome of cancer cells via interactions with other transcription factors. One of these interacting partners is ETS2. ETS2 belongs to the ETS transcription factor family, which has 28 family members. This family is characterized by their affinity for an ETS binding site (EBS). EBS’s are present in 50% of all mutant p53 occupied promoters. Other ETS family members have also been linked to mutant p53 but these interactions have either been deemed as weak (ETS1) or have yet to be identified as direct (ERG). To determine which ETS proteins interact with mutant p53 I conducted affinity pull-down assays using purified ETS proteins and purified mutants of p53. My data shows that several ETS proteins interact with mutant p53 better than ETS2. I then sought to determine which residues are important for this interaction through truncation studies in which I used purified truncations of ETS proteins and purified mutants of p53. I found that ERG, one protein that strongly interacted with mutant p53, had two interaction interfaces. This may explain why the interaction is strong. My next step was to determine which ETS proteins are responsible for the targeting of mutant p53 to the genome. To address the requirement for ETS to recruit mutant p53 to chromatin I performed chromatin immunoprecipitation sequencing studies in the presence or absence of different ETS factors to determine differences in mutant p53 binding. For these studies I knocked down ETS2 or ERG prior to performing p53 ChIP-Seq to determine differences in p53 binding to chromatin under these conditions. My analyses of these data indicate that each of the conditions resulted in different p53 binding patterns in the ChIP-Seq and that there is a requirement for ETS in mutant p53 binding.My studies have demonstrated that ETS proteins interact with mutant p53 and that this interaction seems to be required for mutant p53 binding to the genome. My future work will test phenotypes related to ETS/mutant p53 interactions. Ultimately, if ETS/mutant p53 interactions are deemed important for oncogenic function, these will be attractive targets for future drug development. Citation Format: Stephanie Metcalf, Stevie Morris, Peter Hollenhorst. Mechanisms of mutant p53 targeting to the genome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2365.
Abstract 5722: Targeting the mRNA endonuclease CPSF73 inhibits breast cancer cell migration and invasion
Authors: Huiyun Liu, Daniel Heller-Trulli, Claire Moore
Journal: Cancer Research (2022)

Abstract Cleavage by the endonuclease CPSF73 and polyadenylation of nascent RNA is an essential step in co-transcriptional mRNA maturation, and abnormal poly(A) site choices have been associated with human diseases, including cancer. Recent work has identified CPSF73 as a promising drug target for inhibiting the growth of specific cancers, and higher level of CPSF73 correlates to poor survival in breast cancer patients. However, our understanding of the regulation of CPSF73 is still at an early stage. Here, we report that a HECT-like E3 ligase, UBE3D, participates in stabilizing CPFS73 protein by preventing its ubiquitin-mediated degradation by the proteasome. Depletion of UBE3D in both non-cancer cells and cancer cells leads to CPSF73 downregulation, a pre-mRNA cleavage defect and dysregulated gene expression. UBE3D dysfunction or chemical inactivation of CPFS73 inhibited migration and invasion as well as stem cell renewal phenotypes in vitro in triple negative breast cancer cells. In addition, genetic overexpression of CPSF73 promoted breast cancer stemness and knocking down of CPSF73 inhibited stem cell renewal property. Together, our findings indicate that targeting the pre-mRNA processing nuclease CPSF73 has potential for breast cancer therapy. This work was supported by the NSF grant NS0224 to C. Moore and the NIH grant R01 GM101010-01A1 to C. Moore. Citation Format: Huiyun Liu, Daniel Heller-Trulli, Claire Moore. Targeting the mRNA endonuclease CPSF73 inhibits breast cancer cell migration and invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5722.
Abstract 3293: In vitro cellular and molecular effects of oncolytic vaccinia virus in clear and non-clear cell renal cell carcinoma
Authors: Yuqi Jing, F Bustamante Guerrero, Jaime Merchan
Journal: Cancer Research (2022)

Abstract Oncolytic vaccinia virus has several advantages over other OV platforms, including an efficient life cycle, multiple mechanisms of viral spread, large genome, allowing acceptance of foreign therapeutic DNA inserts, and proven safety in humans, due to its use as smallpox vaccine. JX-594 (Pexavec, SillaJen) is an attenuated (TKdeactivated ) oncolytic vaccinia VV, engineered to express GM-CSF and to selectively target tumor over non-tumor tissues. It is currently being investigated as a novel therapeutic option in patients with advanced Renal Cell Carcinoma (RCC, NCT03294083). The present study was undertaken to investigate the effects of JX-954 in a panel of clear and non-clear cell RCC cell lines and characterize the potential mechanisms of JX-594 oncolysis in vitro. We evaluated the oncolytic potency of JX-594 in human clear cell RCCs (VHL mutant 786-0, A498, VHL wild type Caki-1), non-clear cell RCC (ACHN, papillary RCC, and UOK-262, an FH deficient papillary RCC cell) and murine renal cancer cells (RENCA). Potent and persistent cytotoxic effects were induced by JX-594 in all human RCC cells, regardless of the histological subtype, and by mJX-594 (a Western Reserve strain of vaccinia virus expressing murine GMCSF) in RENCA cells. Moreover, we observed efficient viral replication in human (786-0, ACHN) and murine (RENCA) cells, confirming RCC permissiveness to viral infection. Functional proteomics analysis of JX-594 treated 786-0 cells was performed by reverse phase protein array (RPPA) to gain knowledge on potential mechanisms of viral oncolysis. JX-594 treatment had significant effects on the expression levels of proteins related to inducing cell cycle, apoptosis, necrosis, Akt signaling, MAPK signaling, autophagy and stress induction. In particular, the proteins related to cell cycle (Wee1, Cdc25c, CHK1/2, and Cyclin B1) and Akt signaling (PI3K, mTOR, Rictor and FOXO), MAPK signaling (JAK2, PAK1, FAK and MEK1) were down regulated, while proteins involved in apoptosis and necrosis were upregulated. In summary, our studies show that human and murine renal cancer cells are permissive to infection and replication by JX-594 and mJX-594, which induce potent oncolytic effects in clear and non-clear cell RCC, effects associated with significant modulation of RCC pathways associated with cell cycle, proliferation, and survival and stress responses. Citation Format: Yuqi Jing, F Bustamante Guerrero, Jaime Merchan. In vitro cellular and molecular effects of oncolytic vaccinia virus in clear and non-clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3293.
Abstract 1484: Emerging microRNAs as biomarkers for colorectal cancer diagnosis: A meta-analysis
Authors: Sofia Fathi, Fadila Guessous, Mehdi Karkouri
Journal: Cancer Research (2022)

Abstract Background: Colorectal cancer (CRC) is the second leading cause of cancer deaths worldwide. The current method of clinical screening is mainly based on colonoscopy. However, many CRC patients are unwilling to undergo colonoscopy because of the high procedure cost and the discomfort during examination. Therefore, it appears necessary to find novel and non-invasive biomarkers that would improve CRC early detection. MicroRNAs (miRNAs) are a class of non-coding RNAs with critical regulatory roles in fundamental cellular processes, such as proliferation, migration, and apoptosis. They can act as potential oncogenes or tumor suppressors in cancer development. Numerous studies have shown significant differences in miRNAs expression in serum or plasma of CRC patients and healthy subjects. Thus, the potential use of circulating miRNAs as diagnostic biomarkers in CRC seems to be a fast and relevant alternative to traditional and invasive methods. Here, we reviewed selected studies which identified dysregulated circulating miRNAs in CRC and evaluated their diagnostic value. Methods: This meta-analysis study was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The articles were searched in online databases such as PubMed, Google Scholar to identify all eligible studies that evaluated the diagnostic value of miRNAs for CRC. Then we explored the diagnostic accuracy of each miRNA using the random-effects model to estimate the pooled sensitivity (Se), specificity (Sp), Positive likelihood ratio (PLR) and Negative likelihood ratio (NLR) and the area under the curve (AUC), along with their corresponding 95% confidence intervals (CIs). The statistical analyses were performed using the Review Manager (Revman) 5.4 software and the Meta Disc software. Results: Thirteen studies involving five microRNAs were included in our analysis. Our results suggested that serum miR-29a levels showed great potential as a high diagnostic biomarker for CRC. The overall pooled sensitivity, specificity, area under the curve (AUC), PLR and NLR of circulating miR-29a were 69.75%, 88.25%, 0.8351, 5.93 and 0.342 respectively. Conclusion: miRNAs have become increasingly recognized molecular tools in CRC diagnosis. According to our results, circulating miR-29a level has potential value for early detection and might be used as a novel diagnostic biomarker for CRC in combination with other biomarkers. Citation Format: Sofia Fathi, Fadila Guessous, Mehdi Karkouri. Emerging microRNAs as biomarkers for colorectal cancer diagnosis: A meta-analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1484.
Abstract 2425: Mechano-response via ATP alters calcium signaling in breast epithelial cells with oncogenic KRas mutation
Authors: Makenzy Mull, Stephen Pratt, Rachel Lee, Abanoub Gad, Katarina Chang, David Annis, Keyata Thompson, Michele Vitolo, Liron Boyman, Stuart Martin
Journal: Cancer Research (2022)

Abstract The majority of breast cancer patient deaths occur when tumor cells migrate away from the primary tumors and disseminate metastatically. Cancer cells at the invasive front mimic the behaviors of non-tumorigenic epithelial cells at wound edges but show less coordinated migration comparatively. While most wound healing studies use a timeframe of 24-48 hours, our previous studies have shown that ATP released from wounded cells initiates a calcium (Ca2+) signal within seconds that spreads to neighboring cells through activation of the P2Y2 surface receptor. RNAseq data of MCF10A mammary epithelial cells with stepwise mutations of PTEN knockout and KRas activation alone or in combination, demonstrate that P2Y2 is downregulated specifically by active KRas. Fluorescence microscopy was used to measure Ca2+ signaling and mitochondrial membrane potential in parental and mutant MCF10A cells. Change in total fluorescence was measured and compared to baseline using Fluo-4, a Ca2+ fluorescent indicator, and TMRM (tetramethylrhodamine, methyl ester), a fluorescent mitochondrial membrane potential dye on Nikon analysis software. We show that KRas activation disrupts ATP stimulation and Ca2+ signaling. This change was further quantified using a FlexStation III plate reader with Fluo-4 to read specific fluorescent changes in Ca2+ after ATP addition. ATP-stimulated Ca2+ was also disrupted in other breast tumor cell lines harboring Ras activating mutations, MDA-MB-231 and MDA-MB-436, both showing a similar decrease in P2Y2 expression. These data show that ATP stimulation can be used to further understand the differences in Ca2+ signaling and mechanical-response between normal breast epithelial cells and cancer cells. Clarifying these molecular mechanisms could reveal targets for new cancer treatments, especially since 90% of human tumors are epithelial carcinomas. Citation Format: Makenzy Mull, Stephen Pratt, Rachel Lee, Abanoub Gad, Katarina Chang, David Annis, Keyata Thompson, Michele Vitolo, Liron Boyman, Stuart Martin. Mechano-response via ATP alters calcium signaling in breast epithelial cells with oncogenic KRas mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2425.
Abstract 879: SLFN12-mediated depletion of tRNA-Leu-TAA by velcrin treatment induces ribosome pausing at Leu-TTA codons and represses global translation initiation
Authors: Stephanie Hoyt, Sooncheol Lee, Joseph McGaunn, Andrew Cherniack, Matthew Meyerson, Heidi Greulich
Journal: Cancer Research (2022)

Abstract Velcrin compounds kill cancer cells expressing high levels of PDE3A and SLFN12 by inducing complex formation between these two proteins, but the mechanism of cancer cell killing by the PDE3A-SLFN12 complex is not fully understood. We previously determined that SLFN12 is an RNase, that PDE3A binding upregulates SLFN12 RNase activity, and that SLFN12 RNase activity is required for velcrin response. Here, we report that the depletion of tRNA-Leu-TAA by velcrin treatment induces ribosome pausing at Leu-TTA codons and global inhibition of protein synthesis. We performed ribosome profiling in HeLa cells treated with DMSO or DNMDP and found that ribosome footprints containing Leu-TTA codons at the A-site of the ribosome were significantly more abundant in DNMDP-treated cells than in cells treated with DMSO, indicating a pausing or stalling of ribosomes at Leu-TTA upon velcrin treatment. Although the overall number of ribosome pausing sites across the transcriptome was doubled by DNMDP treatment, ribosome pausing at Leu-TTA was increased &amp;gt 1000-fold, also resulting in an increased number of genes with TTA pause sites. Even though Leu-TTA is a rare codon, over 70% of all transcripts contain at least one TTA codon, implying that ribosome pausing at TTA codons could directly impact many genes. Genes with TTA pause sites most enriched upon velcrin treatment prominently include those involved in control of mRNA translation and protein homeostasis. These results imply that, in addition to direct effects on mRNA translation due to ribosome pausing, indirect effects could occur due to decreased availability of particular components of the translation machinery, resulting in a widespread impact on protein synthesis. To test our hypothesis, we measured the effects of velcrin treatment on nascent protein abundance. Treatment of HeLa cells with DNMDP resulted in downregulation of newly synthesized proteins, whereas no significant changes in total protein content were observed. Downregulation of protein translation was observed only in velcrin-sensitive cell lines, indicating that inhibition of protein translation could be the mechanism of action of cancer cell killing by PDE3A-SLFN12 complex formation. Citation Format: Stephanie Hoyt, Sooncheol Lee, Joseph McGaunn, Andrew Cherniack, Matthew Meyerson, Heidi Greulich. SLFN12-mediated depletion of tRNA-Leu-TAA by velcrin treatment induces ribosome pausing at Leu-TTA codons and represses global translation initiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 879.
Abstract 1406: Design and synthesis of novel cardiac glycosides by targeting the DNA damage response for cancer therapy
Authors: Diana Ainembabazi, Xinran Geng, Navnath Gavande, YouWei Zhang, John Turchi
Journal: Cancer Research (2022)

Abstract Cardiac Glycosides (CGs) are used to treat congestive heart disease. Their application has since been extended to cancer treatment. While the mechanism of action is still unknown, it was previously believed that Na+/K+ ATPase might play a crucial role in cancer mitigation. However, we recently reported that cardiac glycosides could specifically enhance the anti-cancer effect of chemotherapy in KRAS mutant lung cancer by inhibiting the DNA Damage Response (DDR), and these effects were independent of the Na+/K+ ATPase. Mechanistically, we showed that cardiac glycosides induced the degradation of UHRF1, an important player in promoting DNA double strand break (DSB) repair through homologous recombination. These results suggest the promise of derivatizing cardiac glycosides into potential chemo sensitizing agents. Yet, one of the major challenges with these compounds is their cardiotoxicity. This has created a need for developing a strategy to generate less cardiotoxic drugs that are effective in inhibiting the DNA damage response to safe and effective anticancer activity. Herein we report a multi-step synthetic route utilizing k-strophanthidin as the initial building block. A systematic structural design was applied that included modification of the sugar moiety, glycoside linker, stereochemistry, and lactone ring to create a library of O-glycosides and MeON-neoglycosides. These molecules were screened for anti-cancer properties by exploring their influence on the signaling/expression of various downstream kinases in the DDR pathway. We discovered the inhibitory activity of O-glycosides to be more potent than the MeON-neoglycosides or benzylidene-lactone modified compounds. These results demonstrate the ability to chemically synthesize CG derivatives to optimize for anticancer activity with the goal of identifying less cardiotoxic CGs. Citation Format: Diana Ainembabazi, Xinran Geng, Navnath Gavande, YouWei Zhang, John Turchi. Design and synthesis of novel cardiac glycosides by targeting the DNA damage response for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1406.